Therapeutic Options to Prevent Severe COVID-19 in Immunocompromised People - Clinician Outreach and Communication Activity (COCA) Webinar ...
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Centers for Disease Control and Prevention Center for Preparedness and Response Therapeutic Options to Prevent Severe COVID-19 in Immunocompromised People Clinician Outreach and Communication Activity (COCA) Webinar Thursday, August 12, 2021
Free Continuing Education
▪ Free continuing education is offered for this webinar.
▪ Instructions on how to earn continuing education will be provided at the end of the
call.
Continuing Education Disclaimer
▪ In compliance with continuing education requirements, CDC, our planners, our presenters, and
their spouses/partners wish to disclose they have no financial interests or other relationships
with the manufacturers of commercial products, suppliers of commercial services, or
commercial supporters.
▪ Planners have reviewed content to ensure there is no bias.
▪ The presentation will not include any discussion of the unlabeled use of a product or a product
under investigational use except parts of the presentation will focus on monoclonal antibodies
that are not FDA approved but are FDA authorized under Emergency Use Authorization (EUA)
and there will be mention of COVID-19 serology tests that have FDA EUA and have been used
for post-vaccine serology determinations for clinical trials and research studies (as noted in
published or pre-print articles).
▪ CDC did not accept commercial support for this continuing education activity.
Objectives
At the conclusion of today’s session, the participant will be able to accomplish
the following—
1. Describe FDA’s role in issuing EUA for Casirivimab/Imdevimab.
2. Outline the process for ordering and distributing Casirivimab/Imdevimab.
3. Discuss findings of studies on mAbs for COVID-19 (published or in
unpublished pre-print).
4. Describe the National Institutes of Health (NIH) COVID-19 Treatment
Guidelines’ Panel’s recommendations on using monoclonal antibodies to
treat non-hospitalized patients with mild-to-moderate COVID-19.
5. List options for post-exposure prophylaxis use of Casirivimab/Imdevimab.
To Ask a Question
▪ Using the Zoom Webinar System
– Click on the “Q&A” button
– Type your question in the “Q&A” box
– Submit your question
▪ If you are a patient, please refer your question to your healthcare provider.
▪ If you are a member of the media, please direct your questions to
CDC Media Relations at 404-639-3286 or email media@cdc.gov.
Today’s Presenters
▪ Elliot Raizes, MD ▪ Colin Shepard, MD
Task Force Lead CDC Liaison to the Assistant Secretary for Preparedness and
Health Services and Worker Safety Task Force Response (ASPR)
COVID-19 Response Center for Preparedness and Response
Centers for Disease Control and Prevention Centers for Disease Control and Prevention
▪ Adi V. Gundlapalli, MD, PhD ▪ Rajesh Gandhi, MD
Co-Lead, Serology and Correlates of Protection Tiger Team, Director, HIV Clinical Services and Education, Massachusetts
COVID-19 Response General Hospital
Chief Public Health Informatics Officer Professor of Medicine, Harvard Medical School
Center for Surveillance, Epidemiology, and Laboratory
Services
Centers for Disease Control and Prevention
▪ John Farley, MD, MPH
Director, Office of Infectious Diseases
Center for Drug Evaluation and Research
Office of New Drugs
U.S. Food and Drug Administration
Resources: NIH COVID-19 Treatment Guidelines
▪ Anti-SARS-CoV-2 Monoclonal Antibodies
– Visit https://bit.ly/3lRDyKX
▪ Therapeutic Management of Nonhospitalized Adults With COVID-19
– Visit https://bit.ly/3gdjJdJ
▪ Therapeutic Management of Hospitalized Adults With COVID-19
– Visit https://bit.ly/3sgC7qQ
7
Serological Testing Adi V. Gundlapalli, MD, PhD Chief Public Health Informatics Officer Center for Surveillance, Epidemiology, and Laboratory Services Centers for Disease Control and Prevention August 12, 2021 Clinician Outreach and Communication Activity Call
SARS-CoV-2 Serology
▪ SARS-CoV-2 binding antibody assays
– Currently 87 individual emergency use authorizations (EUA) from FDA
– Most are qualitative assays; 12 are semi-quantitative; one is quantitative
– Most measure IgG antibodies to SARS-CoV-2; some measure IgM and IgG
– These tests assess antibodies to viral nucleocapsid protein (N), spike protein (S), or
receptor binding domain protein (RBD)
▪ The current indication for these serology tests as stated in the EUA letter
– “For use as an aid in identifying individuals with an adaptive immune response to SARS-
CoV-2, indicating recent or prior infection”
https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-
serology-and-other-adaptive-immune-response-tests-sars-cov-2#individual-serological 9
Overview of the Adaptive Humoral Immune Response 1. Antigen ingestion and processing by antigen presenting cells; presentation to and stimulation of T helper cells 2. T helper cells stimulate B cells; direct activation of B cells also occurs 3. B cells mature into plasma cells; memory B cells are also generated 4. Antibodies are produced; IgM, then switch to IgG Binding antibodies, subset are neutralizing
Immune Response to SARS-CoV-2
▪ Antigen-specific antibodies
– Detection acknowledges a significant and measurable end-product of the complex machinery
of the adaptive immune system (in commercial assays)
• False positives may occur
– Knowledge of absence of antibodies is informative
• Disruption in the adaptive immune response cascade can occur
• False negatives may occur due to antibody decay or assay performance
▪ None of the commercially available serology assays are FDA-approved nor
recommended for assessing protective immunity
– Established or accepted serologic correlates of protection are pending at this time
– Only one quantitative IgG assay approved for results that are traceable to an international
standard (to quantify and to compare results across labs and assays)
▪ Host response includes innate and cellular immune responses
https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html
https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html#laboratory-testing
Open Forum Infect Dis. Jan 2021;8(1):ofaa555. doi:10.1093/ofid/ofaa555Immune responses to COVID-19 vaccinations in
immunocompromised people
▪ Underlying immune compromise or therapies disrupt the adaptive immune response
▪ Post-vaccine serological testing has been performed as part of clinical trials or research studies
– The clinical utility of post-vaccination serological testing has not been established
▪ Evidence of decreased production of binding and neutralizing antibodies to COVID-19 vaccination
(small N in individual studies)
– Dialysis patients – Transplant patients
– Chronic liver disease • Solid organ
– Hematology-Oncology patients • Hematopoietic stem cell
– Immunosuppressive therapies transplant patients
– Variability noted based on severity of underlying immunocompromise and therapy
▪ Cellular immune responses are also impaired
https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html#laboratory-testing
Reviewed in https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/07-COVID-Oliver-508.pdf
J Hepatol. Apr 2021;74(4):944-951. doi:10.1016/j.jhep.2021.01.032Serological correlates of protection or risk for
breakthrough infections
▪ What we know
– From publications on serology, vaccine effectiveness, and breakthrough infections (small N in individual
studies)
– Consistent relationship between quantitative binding antibody and neutralizing antibody levels
– Neutralizing and binding antibody levels correlate with protection or risk of breakthrough infection after
vaccination in cohorts of individuals
– Need for higher levels of neutralizing antibodies for variants of concern
– Binding antibodies may be a practical solution as neutralizing antibody assays are not readily available
▪ Not yet known
– Threshold levels or ranges such as “% protection above a certain level or in this range of antibodies” are
not yet available
– Impact of variants on estimating and setting levels of antibodies for protection or risk
– Heterogeneity by age, race/ethnicity, immunocompromise status
▪ Limitation: Availability of approved quantitative binding assays with results that are traceable to certified
WHO international standard reference materials is limited
Nat Med. Jul 2021;27(7):1205-1211. doi:10.1038/s41591-021-01377-8 Nature. Jul 8 2021;doi:10.1038/s41586-021-03777-9
N Engl J Med. Jul 28 2021;doi:10.1056/NEJMoa2109072 medRxiv. 2021:2021.06.21.21258528. doi:10.1101/2021.06.21.21258528
Vaccine. Jul 22 2021;39(32):4423-4428. doi:10.1016/j.vaccine.2021.05.063 medRxiv. 2021:2021.08.09.21261290. doi:10.1101/2021.08.09.21261290 13Summary
▪ Currently available commercial serology assays for SARS-CoV-2 are not authorized nor
recommended for assessing protective immunity in natural infections or after
vaccination
– If ordering or reviewing serology test results, please note that a positive test for spike protein could
indicate prior infection and/or vaccination
– To evaluate for evidence of prior infection in an individual with a history of COVID-19 vaccination, an
assay that specifically evaluates antibody to the nucleocapsid protein should be used
▪ Binding and neutralization antibody results after COVID-19 vaccinations have been reported from
clinical trials and research studies
– Adaptive immune responses to COVID-19 vaccination are sub-optimal in immunocompromised
people
– Variability noted based on severity of underlying immunocompromise and therapy
▪ Data on serological correlates of protection are now being reported
– Population thresholds pending for binding and neutralizing antibodies
– Interpretation and extrapolation to immunocompromised people will be challenging
14Thank you For more information, contact CDC 1-800-CDC-INFO (232-4636) TTY: 1-888-232-6348 www.cdc.gov
Disclaimer
The findings and conclusions
in this report are those of the
author(s) and do not
necessarily represent the
official position of the
Centers for Disease Control
and Prevention (CDC).
cdc.gov/coronavirusFDA Emergency Use Authorization of REGEN-COV
(casirivimab and imdevimab)
for Treatment and Post-Exposure Prophylaxis of
COVID-19
CDC Clinician Outreach Call – August 12, 2021
John Farley, MD, MPH
Director, Office of Infectious Diseases, Office of New Drugs, CDERCasirivimab and imdevimab are recombinant human IgG1 monoclonal antibodies
that target the receptor binding domain of the spike protein of SARS-CoV-2.
Treatment Authorization (Nov. 21, 2020)
…for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in
adult and pediatric patients (12 years of age and older weighing at least 40 kg)
with positive results of direct SARS-CoV-2 viral testing, and who are at high risk
for progression to severe COVID-19, including hospitalization or death.
Limitation of Authorized Use
• REGEN-COV (casirivimab and imdevimab) is not authorized for use in patients:
o who are hospitalized due to COVID-19, OR
o who require oxygen therapy due to COVID-19, OR
o who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic
oxygen therapy due to underlying non-COVID-19 related comorbidity.
18Treatment Dosage
• The authorized dosage is 600 mg of casirivimab and 600 mg of imdevimab
administered together as a single intravenous infusion or by subcutaneous
injection as soon as possible after positive SARS-CoV-2 viral testing and within
10 days of symptom onset
• For treatment, intravenous infusion is strongly recommended. Subcutaneous
injection is an alternative route of administration when intravenous infusion
is not feasible and would lead to delay in treatment.
Link to current FDA Fact Sheets and Reviews: https://bit.ly/2VNLFx3
19Post-Exposure Prophylaxis Authorization
(July 30, 2021)
…in adult and pediatric individuals (12 years of age and older weighing at least
40 kg) for post-exposure prophylaxis of COVID-19 in individuals who are at high
risk for progression to severe COVID-19, including hospitalization or death, and
are:
Not fully vaccinated or who are not expected to mount an adequate immune
response to complete SARS-CoV-2 vaccination (for example, individuals with
immunocompromising conditions including those taking immunosuppressive
medications) and
❑ have been exposed to an individual infected with SARS-CoV-2 consistent with
close contact* criteria per Centers for Disease Control and Prevention (CDC)
or
❑ who are at high-risk of exposure to an individual infected with SARS-CoV-2
because of occurrence of SARS-CoV-2 infection in other individuals in the same
institutional setting (for example, nursing homes, prisons). 20Post-Exposure Prophylaxis Authorization (Cont.)
(July 30, 2021)
Limitations of Authorized Use
• Post-exposure prophylaxis with REGEN-COV (casirivimab and imdevimab) is not a substitute for
vaccination against COVID-19.
• REGEN-COV (casirivimab and imdevimab) is not authorized for pre-exposure prophylaxis for
prevention of COVID-19.
*Close contact with an infected individual is defined as: being within 6 feet for a total of 15
minutes or more, providing care at home to someone who is sick, having direct physical contact
with the person (hugging or kissing, for example), sharing eating or drinking utensils, or being
exposed to respiratory droplets from an infected person (sneezing or coughing, for example.
21Post-Exposure Prophylaxis Dosage
• The authorized dosage is 600 mg of casirivimab and 600 mg of imdevimab
administered together as a single intravenous infusion or by subcutaneous
injection as soon as possible following exposure to SARS-CoV-2.
• For individuals in whom repeat dosing is determined to be appropriate for
ongoing exposure to SARS-CoV-2 for longer than 4 weeks and who are not
expected to mount an adequate immune response to complete SARS-CoV-2
vaccination, the initial dose is:
• 600 mg of casirivimab and 600 mg of imdevimab by subcutaneous injection or
intravenous infusion followed by subsequent repeat dosing of 300 mg of
casirivimab and 300 mg of imdevimab by subcutaneous injection or intravenous
infusion once every 4 weeks for the duration of ongoing exposure.
22Data Supporting the Post-Exposure
Prophylaxis Authorization
• COV-2069 trial (NCT04452318): This is a randomized, double-blind, placebo-
controlled Phase 3 clinical trial studying REGEN-COV (casirivimab and
imdevimab) for post-exposure prophylaxis of COVID-19 in household
contacts of individuals infected with SARS-CoV-2 (index case).
• COV-2093 trial: This is a randomized, double-blind, placebo-controlled Phase
1 trial evaluating the safety, pharmacokinetics, and immunogenicity of
repeated doses of 600 mg of casirivimab and 600 mg of imdevimab
administered subcutaneously in healthy adult subjects.
23Uses Not Presently Authorized
• There are a number of uncertainties regarding pre-exposure prophylaxis.
– Which patients are unlikely to mount an adequate immune response to complete
SARS-CoV-2 vaccination?
– What is/are the most appropriate intervention(s) for which patients?
• Ongoing and completed clinical trials may be informative.
– NCT04625725: Phase 3 double-blind, placebo-controlled study of AZD7442 for
Pre-exposure Prophylaxis of COVID-19 in Adults (PROVENT) has a listed actual
primary completion date of May 5, 2021.
• Some physicians are requesting uses of REGEN-COV under expanded access that are
not presently authorized under EUA.
– Expanded access criteria under 21CFR 312.305 and 312.310 must be met. (See
CFR Title 21: https://bit.ly/3AvkwhM)
– Sponsor must agree to provide drug. (See compassionate use policy:
https://bit.ly/3yCIffn)
24EUA Requirements
• EUA Declaration: Before FDA may issue an EUA, the HHS Secretary must declare
that circumstances exist justifying the authorization (usually a public health
emergency).
• Criteria for Issuance:
– Agent referred to in the Secretary’s declaration can cause a serious or life-
threatening disease or condition.
– Based on the totality of scientific information available, including data from
adequate and well-controlled trials if available, it is reasonable to believe that the
product “may be effective” to prevent, diagnose, or treat serious or life-
threatening diseases or conditions caused by the threat agent.
– Known and potential benefits of the product, when used to diagnose, prevent, or
treat the disease or condition, outweigh the known and potential risks of the
product. 25Expanded Access Requirements
21 CFR Sec. 312.305 (for all expanded access uses):
FDA must determine that:
(1) The patient or patients to be treated have a serious or immediately life-threatening disease
or condition, and there is no comparable or satisfactory alternative therapy to diagnose,
monitor, or treat the disease or condition;
(2) The potential patient benefit justifies the potential risks of the treatment use and those
potential risks are not unreasonable in the context of the disease or condition to be treated;
and
(3) Providing the investigational drug for the requested use will not interfere with the initiation,
conduct, or completion of clinical investigations that could support marketing approval of
the expanded access use or otherwise compromise the potential development of the
expanded access use.
21 CFR Sec. 312.310 (additional requirements for individual patient use):
(1) The physician must determine that the probable risk to the person from the investigational
new drug (IND) is not greater than the probable risk from the disease or condition; and
(2) FDA must determine that the patient cannot obtain the drug under another IND or
protocol.
26Disclaimer
The findings and conclusions
in this report are those of the
author(s) and do not
necessarily represent the
official position of the
Centers for Disease Control
and Prevention (CDC).
cdc.gov/coronavirusASPR’s Role in Distribution and
Administration of Monoclonal Antibodies
Colin Shepard, MD
U.S. Department of Health and Human Services, Office of the Assistant Secretary for
Preparedness and Response
August 12, 2021As of 08/02/21
Summary of COVID-19 Therapeutics
No Exposed /
Asymptomatic Early Symptomatic Hospital Admission ICU Admission
Illness
Infected
Hospitalized, high Hospitalized,
Hosp. no Hospitalized,
Healthy, no Not hospitalized, no Hospitalized, flow oxygen/non- mechanical
Not hospitalized, with limitations act. medical not on
infection limitations on oxygen invasive ventilation/
problems oxygen
ventilation ECMO
• Casirivimab + Monoclonal Antibodies Remdesivir
Imdevimab (RGN) • Bamlanivimab +
Etesevimab1 (Lilly)
Tocilizumab
• Casirivimab + Imdevimab
(RGN)
• Sotrovimab (GSK/Vir)
FDA
Key: EUA issued
1. National shipment pause on bamlanivimab + etesevimab due to variants, as of 06/25/2021 approved
Saving Lives. Protecting Americans. 29
Unclassified/For Public UseU.S. government (USG) role in distribution of COVID-19
Monoclonal Antibodies (mAbs)
Our goal: Facilitate the effective use of monoclonal antibody therapeutics to reduce COVID-19
hospitalizations
Three outpatient mAbs have been granted EUA for the treatment of COVID-19 based on their
potential to reduce progression to severe disease and hospitalization in patients at high risk:
➢ Post-exposure prophylaxis ➢ Active COVID-19 infection in patients at higher
– REGEN-COV (casirivimab and risk for severe COVID-19 with mild to moderate
imdevimab) symptoms
– REGEN-COV (casirivimab and imdevimab)
– Bamlanivimab/Etesevimab (currently paused1)
– Sotrovimab (commercially available)
HHS/ASPR has oversight responsibility for the fair and transparent allocation and distribution of
REGEN-COV and bamlanivimab/etesevimab
1. National shipment pause of bamlanivimab/etesevimab and etesevimab alone due to variants, as of 06/25/2021
Saving Lives. Protecting Americans. 30
Unclassified/For Public UseUSG-procured therapies are provided at no-cost
➢ Healthcare providers can order product directly through the distributor
AmerisourceBergen at no cost; information on ordering available at www.phe.gov
➢ CMS reimbursement rates have recently been increased to $450 for most outpatient
settings; and $750 when administered in a patient's home
➢ Additional information on reimbursement can be found at
https://go.cms.gov/3fQKOmq
➢ Treatment options for uninsured available from Health Resources & Services
Administration https://bit.ly/3CFcJ2S
Saving Lives. Protecting Americans. 31
Unclassified/For Public UseDisclaimer
The findings and conclusions
in this report are those of the
author(s) and do not
necessarily represent the
official position of the
Centers for Disease Control
and Prevention (CDC).
cdc.gov/coronavirusAnti-SARS CoV-2 Monoclonal Antibodies for
Treatment and Prevention
Rajesh T. Gandhi, MD
Massachusetts General Hospital
Harvard University Center for AIDS Research
Disclosures (for past year): none
Member of the NIH and Infectious Diseases Society of
America COVID-19 Treatment Guidelines Panels
Acknowledgments: Dr. Arthur Kim. Efe AireweleAnti-SARS CoV-2 Monoclonal Antibodies
for Treatment: Rationale
• Delayed production of neutralizing
antibodies correlates with fatal COVID-19
• Would providing passive immunity through
antibody therapy improve clinical
outcomes?
Lucas C et al, Nat Med. 2021 May 5. doi: 10.1038/s41591-021-01355-0. PMID: 33953384.Outpatient Treatment Across the COVID-19 Spectrum
Asymptomatic/ Mild Moderate Severe Critical
Stage/ Presymptomatic Illness Illness Illness illness
Severity:
+ SARS-CoV-2 test but Mild symptoms (e.g., O2 saturation O2 saturation 30/min; lung dysfunction/failure
no dyspnea disease infiltrates >50%
Disease Viral replication
Pathogenesis:
Inflammation
Hypercoagulability
Potential
treatment: Antivirals Anticoagulation?
Antibody therapy Decrease inflammation
Gandhi RT, CID, 2020
Gandhi RT, Lynch J, del Rio C. NEJM 2020Anti-SARS CoV-2 Monoclonal Antibodies for Treatment • Emergency Use Authorizations (EUAs) for treatment of ambulatory patients with mild to moderate COVID-19 at high risk of progression and within 10 days of symptom onset: • Casirivimab + Imdevimab (600/600 mg) (IV administration preferred) • Bamlanivimab + Etesevimab (700/1400 mg) (distribution paused) • Sotrovimab
Anti-SARS CoV-2 Monoclonal Antibodies
for Post-Exposure Prophylaxis
• Casirivimab/imdevimab (subcutaneous or intravenous) for post-exposure
prophylaxis in individuals who are at high risk for progression to severe COVID-
19 and are:
Not fully vaccinated or not expected to mount adequate immune response to
COVID-19 vaccination (e.g., immunosuppressed individuals) AND
❑ Have been exposed* to an individual with COVID-19
or
❑ At high risk of exposure because of occurrence of COVID-19 in same institutional
setting (e.g., nursing homes, prisons)
*Within 6 feet for ≥15 min, providing care at home, direct contact, exposed to respiratory droplets of infected personWhat are the Data for Use of Anti-
SARS CoV-2 Antibodies for
Treatment?Bamlanivimab/Etesevimab: Outpatient Treatment
• Outpatients with mild to moderate COVID-19 within 3 days of first positive test;
1 or more risk factors for developing severe COVID-19 (n=1035)
• IV bamlanivimab 2800 mg/ Time to hospitalization
etesevimab 2800 mg or placebo
Results:
• 70% reduction in COVID-19
hospitalization or any cause of
death by day 29 (PCasirivimab/Imdevimab: Outpatient Treatment
• Outpatients (n=4057) with mild to moderate COVID-19: placebo or intravenous
casirivimab/imdevimab (various doses)
• Modified full analysis set: +PCR; ≥1 risk factor for severe COVID-19
Results:
• In 600/600 mg group, 70%
reduction in COVID-19 COVID hospitalization or all cause death:
1.0% vs. 3.2%
hospitalizations or death
• More rapid resolution in
symptoms in the antibodies
group: 10 vs. 14 days
Weinreich et al., REGEN-COV Antibody Cocktail Clinical Outcomes Study in Covid-19 Outpatients, https://doi.org/10.1101/2021.05.19.21257469Sotrovimab: Outpatient Treatment
• Outpatients with mild to moderate COVID-19 at high risk of hospitalization
(n=583)
• Randomized to receive N Hospitalized/ Percent
death Reduction
sotrovimab or placebo
Sotrovimab 291 3 (1%) 85%
Result: (p=0.002)
• 85% reduction in
Placebo 292 21 (7%) 85%
hospitalization or death (p=0.002)
Gupta A et al, medRxiv preprint, 2021; https://doi.org/10.1101/2021.05.27.21257096What about SARS-CoV-2 Variants?
Variants and Anti-SARS-CoV-2 Antibodies: In Vitro Studies
• Alpha (B.1.1.7): susceptible to the authorized antibodies
• Beta (B.1.351), Gamma (P.1)
• Marked reduction in susceptibility to bam/ete (distribution paused in US)
• Casirivimab/imdevimab, sotrovimab expected to retain activity
• Delta (B.1.617.2)
• Marked reduction in susceptibility to bam; modest reduction in
susceptibility to bam/ete
• Casirivimab/imdevimab, sotrovimab expected to have activity
Clinical impact of in vitro susceptibilities unknown
https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/NIH COVID-19 Treatment Guidelines
What about people who develop COVID-19
after vaccination?
• For people who develop COVID-19 after receiving COVID-19
vaccination, prior vaccination should not affect treatment
decisions, including use of and timing of treatment with
monoclonal antibodies.What are the Data for Use of anti-SARS
CoV-2 Antibodies for Post-exposure
Prophylaxis?Bamlanivimab: Post-exposure prophylaxis—Long-term care facilities
• Phase 3 randomized trial among residents and staff of long-term care facilities
with at least 1 COVID-19 case (n=1175)
Time from infusion to development of
• Randomized to receive IV mild or worse COVID-19 in Residents
bamlanivimab or placebo
Results
• Among residents in the prevention
population, incidence of mild or
worse COVID-19 was 80% lower in
bamlanivimab group (PCasirivimab/Imdevimab: Post-exposure prophylaxis
• Phase 3 placebo-controlled trial
among household contacts of Symptomatic SARS CoV-2 Infection in Participants
who were PCR and antibody negative at baseline
person with positive SARS CoV-2
test within past 96 hours N Events Proportion Risk Reduction
Placebo 752 59 7.8% 81% (pCasirivimab/Imdevimab: Post-exposure prophylaxis (Cont.)
O’Brien, Subcutaneous REGEN-COV Antibody Combination for Covid-19 Prevention, https://doi.org/10.1101/2021.06.14.21258567, 2021What about Patients Hospitalized
Due to COVID-19?Inpatient Treatment Across the COVID-19 Spectrum
Asymptomatic/ Mild Moderate Severe Critical
Stage/ Presymptomatic Illness Illness Illness illness
Severity:
+ SARS-CoV-2 test but Mild symptoms (eg O2 saturation O2 saturation 30/min; lung dysfunction/failure
no dyspnea disease infiltrates >50%
Disease Viral replication
Pathogenesis:
Inflammation
Hypercoagulability
Potential
treatment: Antivirals Anticoagulation?
Antibody therapy Decrease inflammation
Gandhi RT, CID, 2020
Gandhi RT, Lynch J, del Rio C. NEJM 2020Do Monoclonal Antibodies Have Role in
Hospitalized Patients?
• Bamlanivimab monotherapy did not show benefit in hospitalized patients with
COVID-19 (ACTIV-3)
• Subset without neutralizing Abs and with elevated viral levels appeared to
benefit
• Trial of casirivimab/imdevimab in hospitalized patients on high flow
oxygen/mechanical ventilation stopped
• Therapies stopped due to futility (ACTIV-3): Sotrovimab; BRII-196 and BRII-198
• AZD7442: participants continue to be enrolled (ACTIV-3)
ACTIV-3/TICO LY-CoV555 Study Group, NEJM 2020. https://www.medrxiv.org/content/10.1101/2021.07.19.21260559v1. https://www.nih.gov/news-events/news-releases/nih-sponsored-activ-3-clinical-trial-
closes-enrollment-into-two-sub-studies. https://investor.regeneron.com/news-releases/news-release-details/regn-cov2-independent-data-monitoring-committee-recommends.Casirivimab/Imdevimab in Hospitalized Patients: Recovery
• Hospitalized patients (n=9785)
randomized to usual care with
casirivimab 4,000 mg + imdevimab 4,000
mg IV or usual care alone.
Results
• 28-day all-cause mortality: 20% vs. 21% (no
difference)
• In those seronegative for anti-spike protein
antibody, reduction in mortality with
casi/imdev: 24% vs. 30% (rate ratio 0.80;
95% CI, 0.70–0.91; P = 0.001)
https://www.medrxiv.org/content/10.1101/2021.06.15.21258542v1.full.pdfCasirivimab/Imdevimab in Hospitalized Patients
• Casirivimab/imdevimab not yet
authorized for treatment of hospitalized
patients
• We need rapid and reliable serology test
to identify seronegative individuals
• Casirivimab/imdevimab only available
through expanded access program for
Rapidly evolving
hospitalized patients who are not on high information with more to
flow oxygen or mechanically ventilated come ….Anti-SARS CoV-2 Monoclonal
Antibodies in
Immunocompromised PatientsAnti-SARS CoV-2 Monoclonal Antibodies in
Immunocompromised Patients
• Only small proportion of participants in trials were immunocompromised:
• Bamlanivimab/etesevimab phase 3 treatment trial: 6.5%
• Casirivimab/imdevimab phase 3 treatment trials: 3%
• Bamlanivimab post-exposure prophylaxis study: 19% of prevention cohort
• Immunocompromised patients, who may not mount an endogenous antibody
response, may have protracted viral replication
• Anti-SARS CoV-2 monoclonal antibodies may be particularly effective in reducing
viral load in patients who don’t mount their own antibody response
Dougan M et al, NEJM, 2021; Weinreich et al., REGEN-COV Antibody Cocktail Clinical Outcomes Study in Covid-19 Outpatients, https://doi.org/10.1101/2021.05.19.21257469
Cohen M et al, JAMA 2021; Choi B et al, NEJM, 2020; Haidar G and Mellors JW, CID, 2021SARS CoV-2 Viral Load Changes by Baseline Serum Antibody Status
Weinreich et al., REGEN-COV Antibody Cocktail in Outpatients with Covid-19, https://doi.org/10.1101/2021.06.09.21257915, 2021Anti-SARS CoV-2 Monoclonal Antibodies: Summary
Treatment:
• mAbs authorized to treat high-risk outpatients with mild-moderate COVID-19
• Because of variants: casirivimab/imdevimab or sotrovimab
• Not authorized for use in people hospitalized due to COVID-19; may be used in
people hospitalized for reasons other than COVID-19 (see FDA FAQ)
• In the future, mAbs may have role in seronegative hospitalized patients but
need rapid and reliable serologic test
Post-exposure prophylaxis:
• Casirivimab/imdevimab authorized for post-exposure prophylaxis for people who are at
higher risk for severe COVID-19 who are not fully vaccinated or who are not expected to
mount an immune response (e.g., immunocompromised hosts)
https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-frequently-asked-questionsPost-Exposure Prophylaxis and Treatment Across the COVID-19 Spectrum
Exposure Asymptomatic/ Mild Moderate Severe Critical
Presymptomatic Illness Illness Illness illness
+ SARS-CoV-2 test but Mild symptoms (e.g., O2 saturation O2 saturation 30/min; lung dysfunction/failure
no dyspnea disease infiltrates >50%
Viral replication
Therapeutic
Inflammation
anticoagulation?
Casi/imdev Hypercoagulability
Remdesivir
(high risk,
not fully vaccinated Antivirals or Sotrovimab
Casi/imdev Dexamethasone
or (high risk outpatients with mild In some patients: IL-6 inhibitor
immunosuppressed) Antibody
to moderatetherapy
COVID-19) Decreaseorinflammation
Jak inhibitor
Gandhi RT, CID, 2020
Gandhi RT, Lynch J, del Rio C. NEJM 2020COCA Products & Services
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